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Transcription-Coupled Replacement of Histones: Degradation or Recycling?
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Journal of Genetics and Genomics 39 (2012) 575e580
JGG REVIEW
Transcription-Coupled Replacement of Histones: Degradation or Recycling? Yu-Shan Chen, Xiao-Bo Qiu* Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, and College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing 100875, China Received 18 August 2012; revised 9 September 2012; accepted 13 September 2012 Available online 25 September 2012
ABSTRACT Histone modifications are proposed to constitute a “histone code” for epigenetic regulation of gene expression. However, recent studies demonstrate that histones have to be disassembled from chromatin during transcription. Recent evidence, though not conclusive, suggests that histones might be degradable after being removed from chromatin during transcription. Degradation of overexpressed excessive histones, instead of native histones, has been shown to be dependent on proteasomes and ubiquitination. Since the 26S proteasome usually recognizes polyubiquitinated substrates, it is critical to demonstrate whether degradation of histones is mediated by polyubiquitination. Unexpectedly, there is almost no evidence that any ubiquitin ligase can promote polyubiquitination-dependent degradation of constitutive histones. Meanwhile, acetylation and phosphorylation are also associated with histone degradation. This review attempts to summarize the current knowledge on the transcription-coupled degradation of histones and its regulation by posttranslational protein modifications. KEYWORDS: Histone degradation; Ubiquitin; Proteasome; Ubiquitination; Acetylation; Phosphorylation; Gene activation; Transcription
1. INTRODUCTION In eukaryotes, DNA is packaged and ordered into structural units of chromatin, nucleosomes (Luger et al., 1997). In a nucleosome, an octamer of core histones with two separate H2AeH2B dimers and a stable tetramer of two H3eH4 dimmers is wrapped by 146 bp of DNA, whereas the linker histone H1 bridges neighbored nucleosomes (Kornberg and Lorch, 1999). The densely packed nucleosomes enable highly folded DNA to fit within the confines of the nucleus, and provide structural basis for regulating various cellular processes, such as epigenetic regulation of gene expression, cell division, differentiation, and DNA damage response (Campos and Reinberg, 2009). Characterizing the dynamics of nucleosomes is critical for understanding the roles of chromatin in these processes. The pattern of histone modifications * Corresponding author. Tel: þ86 10 5880 8117, fax: þ86 10 5880 7720. E-mail address: [email protected] (X.-B. Qiu).
has been proposed to constitute a “histone code” for epigenetic regulation of gene expression (Jenuwein and Allis, 2001). Degradation of histones not only regulates gene expression, but also associates with cell differentiation, replication, and survival. Thus, the studies on this issue will greatly contribute to the understanding and treatment of various diseases, such as cancer and neurodegenerative disorders. This review attempts to summarize the research progress on nucleosome dynamics, especially on histone degradation during transcription. 2. HISTONES ARE DEGRADABLE Like DNA, histones are semi-conservatively replicated during DNA replication, and were once considered to be nondegradable (Hancock, 1969; Seale, 1975). However, histones are actually not static on the chromatin, but are in a highly dynamic equilibrium, which is critical to genome stability. An excess of histones inhibits transcription, increases the cellular sensitivity to DNA damage, and causes chromosome
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aggregation or loss (Singh et al., 2009). On the other hand, the deficiency of histone synthesis or assembly results in lower efficiency in transcription (Bonner et al., 1988; Steger and Workman, 1999; Singh et al., 2009). Although histone synthesis in S phase of the cell cycle is coupled with DNA synthesis, histones can also be synthesized in a manner independent of DNA synthesis. When DNA synthesis is inhibited, histone synthesis is not completely inhibited (Butler and Mueller, 1973). Histone genes can be transcribed into mRNA in each phase in the cell cycle (Stein et al., 1989). During G1/G0 phase, when no DNA replication occurs, there is still synthesis of a small amount of histone proteins, approximately 5.6%e17.0% in comparison to those in proliferating cells (Bonner et al., 1988). In order to keep histones in quantitative balance, some old histones must be degraded when new histones are synthesized in nonproliferating somatic cells. Clearly, majority of histones in spermatogenic cells are degraded and eventually replaced by protamine during spermatogenesis (Hammoud et al., 2009). Thus, there is no doubt that histones are degradable, even though the underlying mechanisms are unclear. 3. HISTONES CAN BE DEGRADED DURING TRANSCRIPTION The tight compaction of chromatin seems generally repressive to transcription (Felsenfeld and Groudine, 2003), and might block binding of the sequence-specific transcription factors. Thus, during transcription, histones should be removed to open the chromatin structure. Indeed, the H3eH4 tetramer is replaced with the help of chaperone Spt6 during transcription (Kimura and Cook, 2001). The histone H2AeH2B chaperone, FACT (Facilitates Chromatin Transcription), travels with Pol II, binds the H2AeH2B dimers, and causes a quantitative loss of H2AeH2B dimers (Kireeva et al., 2002; Belotserkovskaya and Reinberg, 2004). Alterations in the global transcriptional program by heat shock or a change in carbon source result in an increased nucleosomal occupancy at repressed promoters, and a decreased nucleosomal occupancy at activated promoters (Lee et al., 2004). Nucleosome depletion is actually observed in promoters that recruit transcription factors (Bernstein et al., 2004). For instance, nucleosomes are removed from the PHO5 promoter during transcriptional activation in Saccharomyces cerevisiae (Boeger et al., 2003). Genome-scale profiling of histone H3.3 replacement patterns in Drosophila melanogaster reveals H3.3 replacement over active genes, and actively transcribed genes are depleted of histones at promoters (Mito et al., 2005). Besides promoters, the most highly active genes are often partially depleted of nucleosomes in coding regions (Lee et al., 2004). The measurement of the levels of histone replacement and nucleosomal occupancy at Drosophila homeotic gene clusters suggests that peaks of histone replacement closely correspond to nuclease-hypersensitive sites (Mito et al., 2007). To further investigate nucleosomal disruption and replacement, Deal et al. (2010) introduced a direct method for measuring the genome-wide dynamics of nucleosome
turnover (named CATCH-IT) by covalently attaching tags to capture histones and to detect histone turnover. This method has a remarkable advantage over previous genomic methods, since the behavior of the native proteins are measured. Thus, the measurement is not limited by the time lag during induction, and is able to measure the ‘hottest’ turnover points. Deal’s results reveal that nucleosome turnover is the highest over active gene bodies in Drosophila cells. CATCHIT data demonstrate a quantitative relationship between nucleosome turnover and the origin recognition complex (ORC), suggesting that nucleosome turnover facilitates ORC binding. In summary, the above studies demonstrate that core histones in the nucleosome are replaced (i.e., disassembled and then reassembled) during transcription. Does histone replacement involve any histone degradation or merely recycling of old histones? The answer is still unclear. However, when ectopic histone H3 is induced in G1-arrested S. cerevisiae, newly synthesized ectopic H3 rapidly replaces constitutive H3 in nucleosomes at promoters and chromatin boundary elements (Dion et al., 2007). Since there is no DNA replication in these cells, the old constitutive H3 released from the chromatin would become excessive. Cells usually maintain strict quantitative equilibrium of histones (Singh et al., 2009), and hence, the excessive constitutive H3 must be degraded. Thus, constitutive histones seem to be degradable during transcription, though the process is probably speeded up by overexpressed histones in this case. 4. MECHANISMS FOR HISTONE DEGRADATION DURING TRANSCRIPTION 4.1. Ubiquitineproteasome pathway There are two major pathways of protein degradation in eukaryotic cells, the autophagy pathway and the ubiquitineproteasome pathway. The ubiquitineproteasome pathway is the main system responsible for degradation of intracellular proteins in eukaryotes. It regulates almost all cellular activities including apoptosis, cell cycle, DNA repair, transcription, and immune response. This pathway includes ubiquitin, ubiquitin-activating enzyme (E1), ubiquitin-carrier protein (E2), ubiquitin-protein ligase (E3), proteasomes and deubiquitinating enzymes. Targeting cellular proteins for degradation via the ubiquitineproteasome pathway involves two discrete steps: 1) tagging of the substrate by covalent attachment of multiple ubiquitin moieties to generate a polyubiquitin chain as degradation signal, and 2) recognizing and degrading the tagged protein by 26S proteasome complex (Goldberg, 2005) (Fig. 1). Ubiquitin is a small conserved protein containing 76 amino-acid residues, and has been found in almost all eukaryotic cells. Polyubiquitination is an enzymatic process in which a lysine residue in the targeted protein is tagged with a polyubiquitin chain by the sequential actions of E1, E2, and E3. Then the polyubiquitin chain is recognized specifically by the 26S proteasome, which consists of a catalytic 20S core
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Fig. 1. Ubiquitineproteasome pathway. In the ubiquitineproteasome pathway, the substrate is first covalently attached with a multi-ubiquitin chain by the sequential actions of E1, E2, and E3, and then the polyubiquitinated substrate is recognized and degraded into small peptides by the 26S proteasome. Ub: ubiquitin; E1: ubiquitin-activating enzyme; E2: ubiquitin-carrier protein; E3: ubiquitin-protein ligase.
particle (CP) and one or two regulatory 19S regulatory particles (RP). The 20S CP, which is a barrel-shaped structure composed of four stacked rings, catalyzes the cleavage of substrates. The 19S complex, which binds to one or both ends of the 20S particle, mediates the binding, deubiquitination, unfolding, and translocation of substrates (Glickman and Ciechanover, 2002; Qiu et al., 2006). Ubiquitin ligase (E3) is responsible for the spatio-temporal specificity of targeted protein ubiquitination, mediating the degradation of substrate by the 26S proteasome indirectly. There are two major classes of E3s, namely RING (Really Interesting New Gene) finger domain-containing E3s and HECT (homologous to E6-AP C-terminus) domain-containing E3s. The former E3s serve as scaffold proteins in creating a link between E2 and the substrate, thus permitting the active ubiquitin to be transferred from E2 to the substrate. In this process, the RING finger domain interacts with E2. The latter E3s require a free thiol group with a cysteine residue in the HECT domain for transferring the ubiquitin from E2 to E3, and subsequently the ubiquitin is transferred from E3 to the substrate. 4.2. Regulation of histone degradation by ubiquitination Histones can be ubiquitinated by ubiquitin ligases. H2A is the first protein identified to be ubiquitinated, and its ubiquitination site is Lys119, a highly conserved residue located at its Cterminus. The ubiquitination site of human H2B has been mapped to Lys 120, and 5%e15% of total H2A and 1%e2% of H2B have been reported to be ubiquitinated in various higher eukaryotic organisms. Ubiquitination on H3 and H1 has also been reported (Zhang, 2003). There are many reported ubiquitin ligases that promote histone monoubiquitination, such as
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Rad6eBre1 for histone H2B and hPRC1L complex (consisting of Ring1, Ring2, Bmil and HPH2) for histone H2A (de Napoles et al., 2004; Giannattasio et al., 2005). Monoubiquitination usually does not mediate proteasomal degradation. A chain of at least 4 ubiquitin moieties is usually required for specific recognition of the substrate by the 26S proteasome. Excess (non-chromatin bound) histones have been found to be rapidly degraded by the proteasome in a Rad53 (radiation sensitive 53) kinase-dependent manner in the budding yeast. Rad53 could phosphorylate core histones in vivo, and contributes to efficient histone degradation. Histones associated with Rad53 are ubiquitinated, and ubiquitin ligase (E3) Tom1 (temperature dependent organization in mitotic nucleus 1) is involved in the degradation of excess histones (Singh et al., 2009). Tom1 is a HECT domaincontaining and UBC4 (E2)-dependent ubiquitin ligase. Other E3s involved in the ubiquitination or degradation of excess histones in yeast include the RING finger domaincontaining proteins, Pep5, Snt2, YKR017C (Hel1, histone ligases 1), and YDR266C (Hel2, histone ligases 2). They all promote histone ubiquitination in vitro. Mutants lacking these ubiquitin ligases are sensitive to histone overexpression as they fail to degrade the excess histones (Singh et al., 2012). In addition, the RING finger domain-containing E3, RNF8, promotes histone monoubiquitination and extensive decondensation of higher-order chromatin structure (Luijsterburg et al., 2012). H2B can also be polyubiquitinated by the Rad6eBre1 ubiquitination machinery at K123 or by an uncharacterized ubiquitin ligase on multiple lysine residues, but the polyubiquitinated H2B is not involved in its degradation (Geng and Tansey, 2008). E3(Histone)/LASU1/HUWE1 is the mammalian ortholog of Tom1 and can catalyze formation of polyubiquitin chains on histones in vitro (Liu et al., 2005). But it is possible that the function of E3(Histone)/LASU1 may be limited to histone monoubiquitination or polyubiquitination of non-histone proteins in vivo, since E3(Histone)/LASU1 is not detectable in spermatids, where histones are largely degraded during spermiogenesis (Liu et al., 2007; Zhang et al., 2011). E3(Histone)/LASU1 is expressed in most tissues, and is localized primarily in the cytoplasm and marginally in the nucleus. However, we cannot rule out the possibility that histones could still be degraded by proteasomes, no matter whether they can only be monoubiquitinated or not ubiquitinated. For example, p21 can be degraded by PA28g-proteasomes in a ubiquitin-independent manner (Jariel-Encontre et al., 2008). Thus, the role of ubiquitineproteasome pathway in histone degradation still remains to be determined. 4.3. Regulation of histone degradation by acetylation Acetylation of histones may promote their turnover. Zee et al. (2010) reported that histone turnover rates vary widely and depend upon the modification status of histones. Acetylated histones have prominently faster turnover rates than general histones and methylated histones. In the PHO5 gene,
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histones are first acetylated and then lost from the promoter upon heat shock, suggesting that modification of histones by acetylation may contribute to nucleosome loss (Reinke and Ho¨rz, 2003). Promoter nucleosomes are transiently acetylated at the HSP82 gene before their eviction in response to heat shock (Zhao et al., 2005). Acetylation in globular core of histone H3 promotes chromatin disassembly during transcription activation (Williams et al., 2008). During spermatogenesis, RNF8, which promotes histone monoubiquitination, induces H4K16 acetylation and nucleosome removal (Lu et al., 2010). Whether acetylation of histones in turn promotes histone polyubiquitylation and the subsequent degradation by proteasomes is still unknown. 4.4. Regulation of histone degradation by phosphorylation and poly-ADP ribosylation Nucleosomes are also found to be displaced from chromatin near the DNA double-strand breaks (DSB), where proteasomes are recruited (Tsukuda et al., 2005). RNF8 mediates binding of adaptor protein MDC1 to histones in a phosphorylation-dependent manner, and promotes ubiquitination of H2AX via its FHA domain in response to DNA damage. The initial phosphorylation and subsequent ubiquitination of H2AX lead to recruitment of the DNA repair machinery to DSB. Furthermore, phosphorylation of H2AX can amplify the DNA damage signal from the DNA damage site to nearby loci (Huen et al., 2007; Mailand et al., 2007). In addition, polyADP ribosylation has been found to activate nuclear 20S proteasome to degrade oxidatively damaged histones in vitro (Ullrich et al., 1999; Catalgol et al., 2010). Thus, phosphorylation and poly-ADP ribosylation might also regulate histone degradation.
5. PERSPECTIVES As carriers of epigenetic codes, histones in somatic cells had been proposed to be stable and semi-conservatively replicated, but recent evidence suggests that they might be degraded at loci where genes are actively transcribed (Dion et al., 2007; Deal et al., 2010). Although there is still no solid evidence for histone degradation during transcription, the integrated information from multiple aspects makes us believe that histones are degradable during transcription. First, there is a tunable reservoir of free histones, which may be regulated by chaperone-mediated autophagic degradation (Cook et al., 2011). Second, excessive free histones can be degraded in a phosphorylation- and ubiquitination-dependent manner in yeast (Singh et al., 2012). Third, upon the induced expression of ectopic histones, constitutive histones might be degraded in a manner coupled with transcription (Dion et al., 2007). Although the mechanism of histone degradation is still unknown, a few studies have tried to uncover this mystery. While specific histone modifications, such as ubiquitination, phosphorylation, and acetylation, may regulate histone degradation, whether histones undergo polyubiquitin-mediated degradation by proteasomes is still in dispute. In any case, the crosstalk among histone modifications appears to be a key issue in understanding how histones are degraded during transcription, and model mechanisms for transcriptioncoupled degradation of histones are proposed in Fig. 2.
4.5. Possibility of histone degradation by nonproteasomal proteases Histones are often monoubiquitinated, whereas monoubiquitination can target various substrates to the lysosome for degradation. For instance, monoubiquitination of the epidermal growth factor receptor (EGFR) promoted by the ubiquitin ligase Cbl is necessary for its lysosomal degradation (Grøvdal et al., 2004). Indeed, soluble histones have recently been suggested to be targeted for degradation by the chaperone-mediated autophagy (Cook et al., 2011). The possibility also exists that histones are degraded by some specific non-proteasomal proteases. Histones in isolated chromatin can be degraded by a neutral protease originated from cytoplasmic organelles (Destree et al., 1975). Normal rat liver chromatin contains a protease activity with a marked preference for histones as substrates (Garrels et al., 1972). A chromatin-associated protease has also been reported in mouse seminiferous tubules, where histones are mostly degraded during spermatogenesis (Faulkner and Bhatnagar, 1987). Evidence related to histone-specific proteases is relatively poor, and more researches are needed for illuminating the mysteries of histone degradation.
Fig. 2. Model mechanisms for transcription-coupled degradation of histones. During transcription, histones are removed from chromatin, and at least some of them are eventually degraded by proteases, such as proteasomes and lysosomes. After transcription, newly synthesized histones and a part of old histones will be recruited into nucleosomes. The eviction of histones from chromatin is regulated by histone posttranslational modifications, such as ubiquitination, acetylation, and phosphorylation. Ub: ubiquitin; P: phosphate; Ac: Acetyl.
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ACKNOWLEDGEMENTS We thank Ya-Yi Xu and Ruo-Yu Wang for assistance in preparing figures in this manuscript. This work was supported by grants from the Ministry of Science and Technology of China (No. 2012CB910300), the National Natural Science Foundation of China (No. 30525033), and the Fundamental Research Funds for the Central Universities of China to X.-B. Q. REFERENCES Belotserkovskaya, R., Reinberg, D., 2004. Facts about FACT and transcript elongation through chromatin. Curr. Opin. Genet. Dev. 14, 139e146. Bernstein, B.E., Liu, C.L., Humphrey, E.L., Perlstein, E.O., Schreiber, S.L., 2004. Global nucleosome occupancy in yeast. Genome Biol. 5, R62. Boeger, H., Griesenbeck, J., Strattan, J.S., Kornberg, R.D., 2003. Nucleosomes unfold completely at a transcriptionally active promoter. Mol. Cell 11, 1587e1598. Bonner, W., Wu, R.S., Panusz, H., Muneses, C., 1988. Kinetics of accumulation and depletion of soluble newly synthesized histone in the reciprocal regulation of histone and DNA synthesis. Biochemistry 27, 6542e6550. Butler, W.B., Mueller, G.C., 1973. Control of histone synthesis in HeLa cells. Biochim. Biophys. Acta 294, 481e496. Campos, E.I., Reinberg, D., 2009. Histones: annotating chromatin. Annu. Rev. Genet. 43, 559e599. ¨ zer, N.K., Grune, T., 2010. Catalgol, B., Wendt, B., Grimm, S., Breusing, N., O Chromatin repair after oxidative stress: role of PARP-mediated proteasome activation. Free Radic. Bio. Med. 48, 673e680. Cook, A.J.L., Gurard-Levin, Z.A., Vassias, I., Almouzni, G., 2011. A specific function for the histone chaperone NASP to fine-tune a reservoir of soluble H3-H4 in the histone supply chain. Mol. Cell 44, 918e927. de Napoles, M., Mermoud, J.E., Wakao, R., Tang, Y.A., Endoh, M., Appanah, R., Nesterova, T.B., Silva, J., Otte, A.P., Vidal, M., 2004. Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev. Cell 7, 663e676. Deal, R.B., Henikoff, J.G., Henikoff, S., 2010. Genome-wide kinetics of nucleosome turnover determined by metabolic labeling of histones. Science 328, 1161e1164. Destree, O., D’Adelhart-Toorop, H., Charles, R., 1975. Cytoplasmic origin of the so-called nuclear neutral histone protease. Biochim. Biophys. Acta 378, 450e458. Dion, M.F., Kaplan, T., Kim, M., Buratowski, S., Friedman, N., Rando, O.J., 2007. Dynamics of replication-independent histone turnover in budding yeast. Science 315, 1405e1408. Faulkner, R., Bhatnagar, Y., 1987. A protease activity is associated with testicular chromatin of the mouse. Biol. Reprod. 36, 471e480. Felsenfeld, G., Groudine, M., 2003. Controlling the double helix. Nature 421, 448e453. Garrels, J.I., Elgin, S.C.R., Bonner, J., 1972. A histone protease of rat liver chromatin. Biochem. Biophys. Res. Commun. 46, 545e551. Geng, F., Tansey, W.P., 2008. Polyubiquitylation of histone H2B. Mol. Biol. Cell 19, 3616e3624. Giannattasio, M., Lazzaro, F., Plevani, P., Muzi-Falconi, M., 2005. The DNA damage checkpoint response requires histone H2B ubiquitination by Rad6eBre1 and H3 methylation by Dot1. J. Biol. Chem. 280, 9879e9886. Glickman, M.H., Ciechanover, A., 2002. The ubiquitineproteasome proteolytic pathway: destruction for the sake of construction. Physiol. Rev. 82, 373e428. Goldberg, A.L., 2005. Nobel committee tags ubiquitin for distinction. Neuron 45, 339e344. Grøvdal, L.M., Stang, E., Sorkin, A., Madshus, I.H., 2004. Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation. Exp. Cell Res. 300, 388e395. Hammoud, S.S., Nix, D.A., Zhang, H., Purwar, J., Carrell, D.T., Cairns, B.R., 2009. Distinctive chromatin in human sperm packages genes for embryo development. Nature 460, 473e478.
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Journal of Genetics and Genomics 39 (2012) 575e580
JGG REVIEW
Transcription-Coupled Replacement of Histones: Degradation or Recycling? Yu-Shan Chen, Xiao-Bo Qiu* Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, and College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing 100875, China Received 18 August 2012; revised 9 September 2012; accepted 13 September 2012 Available online 25 September 2012
ABSTRACT Histone modifications are proposed to constitute a “histone code” for epigenetic regulation of gene expression. However, recent studies demonstrate that histones have to be disassembled from chromatin during transcription. Recent evidence, though not conclusive, suggests that histones might be degradable after being removed from chromatin during transcription. Degradation of overexpressed excessive histones, instead of native histones, has been shown to be dependent on proteasomes and ubiquitination. Since the 26S proteasome usually recognizes polyubiquitinated substrates, it is critical to demonstrate whether degradation of histones is mediated by polyubiquitination. Unexpectedly, there is almost no evidence that any ubiquitin ligase can promote polyubiquitination-dependent degradation of constitutive histones. Meanwhile, acetylation and phosphorylation are also associated with histone degradation. This review attempts to summarize the current knowledge on the transcription-coupled degradation of histones and its regulation by posttranslational protein modifications. KEYWORDS: Histone degradation; Ubiquitin; Proteasome; Ubiquitination; Acetylation; Phosphorylation; Gene activation; Transcription
1. INTRODUCTION In eukaryotes, DNA is packaged and ordered into structural units of chromatin, nucleosomes (Luger et al., 1997). In a nucleosome, an octamer of core histones with two separate H2AeH2B dimers and a stable tetramer of two H3eH4 dimmers is wrapped by 146 bp of DNA, whereas the linker histone H1 bridges neighbored nucleosomes (Kornberg and Lorch, 1999). The densely packed nucleosomes enable highly folded DNA to fit within the confines of the nucleus, and provide structural basis for regulating various cellular processes, such as epigenetic regulation of gene expression, cell division, differentiation, and DNA damage response (Campos and Reinberg, 2009). Characterizing the dynamics of nucleosomes is critical for understanding the roles of chromatin in these processes. The pattern of histone modifications * Corresponding author. Tel: þ86 10 5880 8117, fax: þ86 10 5880 7720. E-mail address: [email protected] (X.-B. Qiu).
has been proposed to constitute a “histone code” for epigenetic regulation of gene expression (Jenuwein and Allis, 2001). Degradation of histones not only regulates gene expression, but also associates with cell differentiation, replication, and survival. Thus, the studies on this issue will greatly contribute to the understanding and treatment of various diseases, such as cancer and neurodegenerative disorders. This review attempts to summarize the research progress on nucleosome dynamics, especially on histone degradation during transcription. 2. HISTONES ARE DEGRADABLE Like DNA, histones are semi-conservatively replicated during DNA replication, and were once considered to be nondegradable (Hancock, 1969; Seale, 1975). However, histones are actually not static on the chromatin, but are in a highly dynamic equilibrium, which is critical to genome stability. An excess of histones inhibits transcription, increases the cellular sensitivity to DNA damage, and causes chromosome
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aggregation or loss (Singh et al., 2009). On the other hand, the deficiency of histone synthesis or assembly results in lower efficiency in transcription (Bonner et al., 1988; Steger and Workman, 1999; Singh et al., 2009). Although histone synthesis in S phase of the cell cycle is coupled with DNA synthesis, histones can also be synthesized in a manner independent of DNA synthesis. When DNA synthesis is inhibited, histone synthesis is not completely inhibited (Butler and Mueller, 1973). Histone genes can be transcribed into mRNA in each phase in the cell cycle (Stein et al., 1989). During G1/G0 phase, when no DNA replication occurs, there is still synthesis of a small amount of histone proteins, approximately 5.6%e17.0% in comparison to those in proliferating cells (Bonner et al., 1988). In order to keep histones in quantitative balance, some old histones must be degraded when new histones are synthesized in nonproliferating somatic cells. Clearly, majority of histones in spermatogenic cells are degraded and eventually replaced by protamine during spermatogenesis (Hammoud et al., 2009). Thus, there is no doubt that histones are degradable, even though the underlying mechanisms are unclear. 3. HISTONES CAN BE DEGRADED DURING TRANSCRIPTION The tight compaction of chromatin seems generally repressive to transcription (Felsenfeld and Groudine, 2003), and might block binding of the sequence-specific transcription factors. Thus, during transcription, histones should be removed to open the chromatin structure. Indeed, the H3eH4 tetramer is replaced with the help of chaperone Spt6 during transcription (Kimura and Cook, 2001). The histone H2AeH2B chaperone, FACT (Facilitates Chromatin Transcription), travels with Pol II, binds the H2AeH2B dimers, and causes a quantitative loss of H2AeH2B dimers (Kireeva et al., 2002; Belotserkovskaya and Reinberg, 2004). Alterations in the global transcriptional program by heat shock or a change in carbon source result in an increased nucleosomal occupancy at repressed promoters, and a decreased nucleosomal occupancy at activated promoters (Lee et al., 2004). Nucleosome depletion is actually observed in promoters that recruit transcription factors (Bernstein et al., 2004). For instance, nucleosomes are removed from the PHO5 promoter during transcriptional activation in Saccharomyces cerevisiae (Boeger et al., 2003). Genome-scale profiling of histone H3.3 replacement patterns in Drosophila melanogaster reveals H3.3 replacement over active genes, and actively transcribed genes are depleted of histones at promoters (Mito et al., 2005). Besides promoters, the most highly active genes are often partially depleted of nucleosomes in coding regions (Lee et al., 2004). The measurement of the levels of histone replacement and nucleosomal occupancy at Drosophila homeotic gene clusters suggests that peaks of histone replacement closely correspond to nuclease-hypersensitive sites (Mito et al., 2007). To further investigate nucleosomal disruption and replacement, Deal et al. (2010) introduced a direct method for measuring the genome-wide dynamics of nucleosome
turnover (named CATCH-IT) by covalently attaching tags to capture histones and to detect histone turnover. This method has a remarkable advantage over previous genomic methods, since the behavior of the native proteins are measured. Thus, the measurement is not limited by the time lag during induction, and is able to measure the ‘hottest’ turnover points. Deal’s results reveal that nucleosome turnover is the highest over active gene bodies in Drosophila cells. CATCHIT data demonstrate a quantitative relationship between nucleosome turnover and the origin recognition complex (ORC), suggesting that nucleosome turnover facilitates ORC binding. In summary, the above studies demonstrate that core histones in the nucleosome are replaced (i.e., disassembled and then reassembled) during transcription. Does histone replacement involve any histone degradation or merely recycling of old histones? The answer is still unclear. However, when ectopic histone H3 is induced in G1-arrested S. cerevisiae, newly synthesized ectopic H3 rapidly replaces constitutive H3 in nucleosomes at promoters and chromatin boundary elements (Dion et al., 2007). Since there is no DNA replication in these cells, the old constitutive H3 released from the chromatin would become excessive. Cells usually maintain strict quantitative equilibrium of histones (Singh et al., 2009), and hence, the excessive constitutive H3 must be degraded. Thus, constitutive histones seem to be degradable during transcription, though the process is probably speeded up by overexpressed histones in this case. 4. MECHANISMS FOR HISTONE DEGRADATION DURING TRANSCRIPTION 4.1. Ubiquitineproteasome pathway There are two major pathways of protein degradation in eukaryotic cells, the autophagy pathway and the ubiquitineproteasome pathway. The ubiquitineproteasome pathway is the main system responsible for degradation of intracellular proteins in eukaryotes. It regulates almost all cellular activities including apoptosis, cell cycle, DNA repair, transcription, and immune response. This pathway includes ubiquitin, ubiquitin-activating enzyme (E1), ubiquitin-carrier protein (E2), ubiquitin-protein ligase (E3), proteasomes and deubiquitinating enzymes. Targeting cellular proteins for degradation via the ubiquitineproteasome pathway involves two discrete steps: 1) tagging of the substrate by covalent attachment of multiple ubiquitin moieties to generate a polyubiquitin chain as degradation signal, and 2) recognizing and degrading the tagged protein by 26S proteasome complex (Goldberg, 2005) (Fig. 1). Ubiquitin is a small conserved protein containing 76 amino-acid residues, and has been found in almost all eukaryotic cells. Polyubiquitination is an enzymatic process in which a lysine residue in the targeted protein is tagged with a polyubiquitin chain by the sequential actions of E1, E2, and E3. Then the polyubiquitin chain is recognized specifically by the 26S proteasome, which consists of a catalytic 20S core
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Fig. 1. Ubiquitineproteasome pathway. In the ubiquitineproteasome pathway, the substrate is first covalently attached with a multi-ubiquitin chain by the sequential actions of E1, E2, and E3, and then the polyubiquitinated substrate is recognized and degraded into small peptides by the 26S proteasome. Ub: ubiquitin; E1: ubiquitin-activating enzyme; E2: ubiquitin-carrier protein; E3: ubiquitin-protein ligase.
particle (CP) and one or two regulatory 19S regulatory particles (RP). The 20S CP, which is a barrel-shaped structure composed of four stacked rings, catalyzes the cleavage of substrates. The 19S complex, which binds to one or both ends of the 20S particle, mediates the binding, deubiquitination, unfolding, and translocation of substrates (Glickman and Ciechanover, 2002; Qiu et al., 2006). Ubiquitin ligase (E3) is responsible for the spatio-temporal specificity of targeted protein ubiquitination, mediating the degradation of substrate by the 26S proteasome indirectly. There are two major classes of E3s, namely RING (Really Interesting New Gene) finger domain-containing E3s and HECT (homologous to E6-AP C-terminus) domain-containing E3s. The former E3s serve as scaffold proteins in creating a link between E2 and the substrate, thus permitting the active ubiquitin to be transferred from E2 to the substrate. In this process, the RING finger domain interacts with E2. The latter E3s require a free thiol group with a cysteine residue in the HECT domain for transferring the ubiquitin from E2 to E3, and subsequently the ubiquitin is transferred from E3 to the substrate. 4.2. Regulation of histone degradation by ubiquitination Histones can be ubiquitinated by ubiquitin ligases. H2A is the first protein identified to be ubiquitinated, and its ubiquitination site is Lys119, a highly conserved residue located at its Cterminus. The ubiquitination site of human H2B has been mapped to Lys 120, and 5%e15% of total H2A and 1%e2% of H2B have been reported to be ubiquitinated in various higher eukaryotic organisms. Ubiquitination on H3 and H1 has also been reported (Zhang, 2003). There are many reported ubiquitin ligases that promote histone monoubiquitination, such as
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Rad6eBre1 for histone H2B and hPRC1L complex (consisting of Ring1, Ring2, Bmil and HPH2) for histone H2A (de Napoles et al., 2004; Giannattasio et al., 2005). Monoubiquitination usually does not mediate proteasomal degradation. A chain of at least 4 ubiquitin moieties is usually required for specific recognition of the substrate by the 26S proteasome. Excess (non-chromatin bound) histones have been found to be rapidly degraded by the proteasome in a Rad53 (radiation sensitive 53) kinase-dependent manner in the budding yeast. Rad53 could phosphorylate core histones in vivo, and contributes to efficient histone degradation. Histones associated with Rad53 are ubiquitinated, and ubiquitin ligase (E3) Tom1 (temperature dependent organization in mitotic nucleus 1) is involved in the degradation of excess histones (Singh et al., 2009). Tom1 is a HECT domaincontaining and UBC4 (E2)-dependent ubiquitin ligase. Other E3s involved in the ubiquitination or degradation of excess histones in yeast include the RING finger domaincontaining proteins, Pep5, Snt2, YKR017C (Hel1, histone ligases 1), and YDR266C (Hel2, histone ligases 2). They all promote histone ubiquitination in vitro. Mutants lacking these ubiquitin ligases are sensitive to histone overexpression as they fail to degrade the excess histones (Singh et al., 2012). In addition, the RING finger domain-containing E3, RNF8, promotes histone monoubiquitination and extensive decondensation of higher-order chromatin structure (Luijsterburg et al., 2012). H2B can also be polyubiquitinated by the Rad6eBre1 ubiquitination machinery at K123 or by an uncharacterized ubiquitin ligase on multiple lysine residues, but the polyubiquitinated H2B is not involved in its degradation (Geng and Tansey, 2008). E3(Histone)/LASU1/HUWE1 is the mammalian ortholog of Tom1 and can catalyze formation of polyubiquitin chains on histones in vitro (Liu et al., 2005). But it is possible that the function of E3(Histone)/LASU1 may be limited to histone monoubiquitination or polyubiquitination of non-histone proteins in vivo, since E3(Histone)/LASU1 is not detectable in spermatids, where histones are largely degraded during spermiogenesis (Liu et al., 2007; Zhang et al., 2011). E3(Histone)/LASU1 is expressed in most tissues, and is localized primarily in the cytoplasm and marginally in the nucleus. However, we cannot rule out the possibility that histones could still be degraded by proteasomes, no matter whether they can only be monoubiquitinated or not ubiquitinated. For example, p21 can be degraded by PA28g-proteasomes in a ubiquitin-independent manner (Jariel-Encontre et al., 2008). Thus, the role of ubiquitineproteasome pathway in histone degradation still remains to be determined. 4.3. Regulation of histone degradation by acetylation Acetylation of histones may promote their turnover. Zee et al. (2010) reported that histone turnover rates vary widely and depend upon the modification status of histones. Acetylated histones have prominently faster turnover rates than general histones and methylated histones. In the PHO5 gene,
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histones are first acetylated and then lost from the promoter upon heat shock, suggesting that modification of histones by acetylation may contribute to nucleosome loss (Reinke and Ho¨rz, 2003). Promoter nucleosomes are transiently acetylated at the HSP82 gene before their eviction in response to heat shock (Zhao et al., 2005). Acetylation in globular core of histone H3 promotes chromatin disassembly during transcription activation (Williams et al., 2008). During spermatogenesis, RNF8, which promotes histone monoubiquitination, induces H4K16 acetylation and nucleosome removal (Lu et al., 2010). Whether acetylation of histones in turn promotes histone polyubiquitylation and the subsequent degradation by proteasomes is still unknown. 4.4. Regulation of histone degradation by phosphorylation and poly-ADP ribosylation Nucleosomes are also found to be displaced from chromatin near the DNA double-strand breaks (DSB), where proteasomes are recruited (Tsukuda et al., 2005). RNF8 mediates binding of adaptor protein MDC1 to histones in a phosphorylation-dependent manner, and promotes ubiquitination of H2AX via its FHA domain in response to DNA damage. The initial phosphorylation and subsequent ubiquitination of H2AX lead to recruitment of the DNA repair machinery to DSB. Furthermore, phosphorylation of H2AX can amplify the DNA damage signal from the DNA damage site to nearby loci (Huen et al., 2007; Mailand et al., 2007). In addition, polyADP ribosylation has been found to activate nuclear 20S proteasome to degrade oxidatively damaged histones in vitro (Ullrich et al., 1999; Catalgol et al., 2010). Thus, phosphorylation and poly-ADP ribosylation might also regulate histone degradation.
5. PERSPECTIVES As carriers of epigenetic codes, histones in somatic cells had been proposed to be stable and semi-conservatively replicated, but recent evidence suggests that they might be degraded at loci where genes are actively transcribed (Dion et al., 2007; Deal et al., 2010). Although there is still no solid evidence for histone degradation during transcription, the integrated information from multiple aspects makes us believe that histones are degradable during transcription. First, there is a tunable reservoir of free histones, which may be regulated by chaperone-mediated autophagic degradation (Cook et al., 2011). Second, excessive free histones can be degraded in a phosphorylation- and ubiquitination-dependent manner in yeast (Singh et al., 2012). Third, upon the induced expression of ectopic histones, constitutive histones might be degraded in a manner coupled with transcription (Dion et al., 2007). Although the mechanism of histone degradation is still unknown, a few studies have tried to uncover this mystery. While specific histone modifications, such as ubiquitination, phosphorylation, and acetylation, may regulate histone degradation, whether histones undergo polyubiquitin-mediated degradation by proteasomes is still in dispute. In any case, the crosstalk among histone modifications appears to be a key issue in understanding how histones are degraded during transcription, and model mechanisms for transcriptioncoupled degradation of histones are proposed in Fig. 2.
4.5. Possibility of histone degradation by nonproteasomal proteases Histones are often monoubiquitinated, whereas monoubiquitination can target various substrates to the lysosome for degradation. For instance, monoubiquitination of the epidermal growth factor receptor (EGFR) promoted by the ubiquitin ligase Cbl is necessary for its lysosomal degradation (Grøvdal et al., 2004). Indeed, soluble histones have recently been suggested to be targeted for degradation by the chaperone-mediated autophagy (Cook et al., 2011). The possibility also exists that histones are degraded by some specific non-proteasomal proteases. Histones in isolated chromatin can be degraded by a neutral protease originated from cytoplasmic organelles (Destree et al., 1975). Normal rat liver chromatin contains a protease activity with a marked preference for histones as substrates (Garrels et al., 1972). A chromatin-associated protease has also been reported in mouse seminiferous tubules, where histones are mostly degraded during spermatogenesis (Faulkner and Bhatnagar, 1987). Evidence related to histone-specific proteases is relatively poor, and more researches are needed for illuminating the mysteries of histone degradation.
Fig. 2. Model mechanisms for transcription-coupled degradation of histones. During transcription, histones are removed from chromatin, and at least some of them are eventually degraded by proteases, such as proteasomes and lysosomes. After transcription, newly synthesized histones and a part of old histones will be recruited into nucleosomes. The eviction of histones from chromatin is regulated by histone posttranslational modifications, such as ubiquitination, acetylation, and phosphorylation. Ub: ubiquitin; P: phosphate; Ac: Acetyl.
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